Abstract Our understanding on the cardiovascular system has been widened over the past decades, but still millions of patients with cardiovascular disease (CVD), the most devastating disease in the United States and the rest of the world, await more effective means to treat the disease. Thus, a comprehensive insight into the mechanisms regulating the function of the cardiovascular system is urgently needed. Previously, we have demonstrated an indispensable role of the transcription factor ETV2 (also known as ER71) in cardiovascular system development. Also, our recent studies with genetically modified mice provide compelling evidence that show ETV2?s potent and novel functions in the vascular regeneration in adults. Mice lacking endothelial ETV2 exhibit significantly impaired new vessel formation in response to tissue injuries including laser-induced eye injury, skin wounding, or hindlimb ischemic injury, which are models for age-related macular degeneration, general wound healing, and peripheral arterial disease, respectively. Moreover, a lentiviral delivery of ETV2 into ischemic hindlimbs leads to an improved recovery of blood flow, augments angiogenic gene expression and enhances vascular regeneration, highlighting a requisite postnatal function of ETV2 in an injury-induced neovascularization. However, current knowledge on mechanisms by which ETV2 functions in the cardiovascular system and vascular regeneration is very limited. Our preliminary results suggest that ETV2 directs the expression of endothelial genes and thus generation of cardiovascular lineages by regulating the status of H3K9 methylation though the interaction with KDM4A, a histone demethylase. In addition, our investigations strongly suggest a functional correlation between the NF?B pathway and ETV2 in mediating injury-induced neovascularization. Furthermore, we have several lines of evidence showing that myelomonocyte ETV2 plays a significant role in neovascularization upon ischemic insults. Building upon these strong and novel evidence as well as tools, we will decipher mechanisms and functions of ETV2, 1) by determining the epigenetic regulatory role of the interaction between ETV2 and KDM4A for cardiovascular lineage generation, 2) by investigating the role of the NF?B as a direct upstream regulator of ETV2 in mouse models of hindlimb ischemia and tumor, 3) by revealing the novel functions of myelomonocyte ETV2, contributing to neovascularization by regulating inflammation. The outcome of this work will reveal uncovered functions of ETV2 in vascular development and functions as well as tissue repair, significantly advancing our limited knowledge on vascular biology. Thus, our findings could lead to the development of novel, effective therapeutic strategies for diseases related to dysfunctional vessel formation, an important translational aspect of the proposed studies.